RESUMEN

The development of new analgesics has been challenging. Candidate drugs often have limited clinical utility due to side effects that arise because many drug targets are involved in signaling pathways other than pain transduction. Here, we explored the potential of targeting protein-protein interactions (PPIs) that mediate pain signaling as an approach to developing drugs to treat chronic pain. We reviewed the approaches used to identify small molecules and peptide modulators of PPIs and their ability to decrease pain-like behaviors in rodent animal models. We analyzed data from rodent and human sensory nerve tissues to build associated signaling networks and assessed both validated and potential interactions and the structures of the interacting domains that could inform the design of synthetic peptides and small molecules. This resource identifies PPIs that could be explored for the development of new analgesics, particularly between scaffolding proteins and receptors for various growth factors and neurotransmitters, as well as ion channels and other enzymes. Targeting the adaptor function of CBL by blocking interactions between its proline-rich carboxyl-terminal domain and its SH3-domain-containing protein partners, such as GRB2, could disrupt endosomal signaling induced by pain-associated growth factors. This approach would leave intact its E3-ligase functions, which are mediated by other domains and are critical for other cellular functions. This potential of PPI modulators to be more selective may mitigate side effects and improve the clinical management of pain.

Asunto(s)

Analgésicos , Transducción de Señal , Humanos , Animales , Analgésicos/farmacología , Analgésicos/química , Transducción de Señal/efectos de los fármacos , Mapas de Interacción de Proteínas/efectos de los fármacos , Dolor Crónico/tratamiento farmacológico , Dolor Crónico/metabolismo , Dolor/metabolismo , Dolor/tratamiento farmacológico

RESUMEN

INTRODUCTION: This review highlights the critical role of the endocannabinoid system (ECS) in regulating neuropathic pain and explores the therapeutic potential of cannabinoids. Understanding the mechanisms of the ECS, including its receptors, endogenous ligands, and enzymatic routes, can lead to innovative treatments for chronic pain, offering more effective therapies for neuropathic conditions. This review bridges the gap between preclinical studies and clinical applications by emphasizing ECS modulation for better pain management outcomes. AREAS COVERED: A review mapped the existing literature on neuropathic pain and the effects of modulating the ECS using natural and synthetic cannabinoids. This analysis examined ECS components and their alterations in neuropathic pain, highlighting the peripheral, spinal, and supraspinal mechanisms. This review aimed to provide a thorough understanding of the therapeutic potential of cannabinoids in the management of neuropathic pain. EXPERT OPINION: Advances in cannabinoid research have shown significant potential for the management of chronic neuropathic pain. The study emphasizes the need for high-quality clinical trials and collaborative efforts among researchers, clinicians, and regulatory bodies to ensure safe and effective integration of cannabinoids into pain management protocols. Understanding the mechanisms and optimizing cannabinoid formulations and delivery methods are crucial for enhancing therapeutic outcomes.

Asunto(s)

Cannabinoides , Endocannabinoides , Neuralgia , Neuralgia/tratamiento farmacológico , Neuralgia/fisiopatología , Humanos , Endocannabinoides/metabolismo , Animales , Cannabinoides/farmacología , Dolor Crónico/tratamiento farmacológico , Dolor Crónico/fisiopatología , Analgésicos/farmacología , Terapia Molecular Dirigida , Receptores de Cannabinoides/metabolismo

RESUMEN

In the pursuit of new lead compounds with fewer side effects than opioids, the novel synthetic phytochemical core, 3,3-dibromoflavanone (3,3-DBF), has emerged as a promising candidate for pain management. Acute assays demonstrated dose-dependent central and peripheral antinociceptive activity of 3,3-DBF through the µ-opioid receptor. This study aimed to explore repeated administration effects of 3,3-DBF in mice and compare them with morphine. Mice were treated with 3,3-DBF (30 mg/kg), morphine (6 mg/kg), or vehicle for 10 days, alongside single-treatment groups. Unlike morphine, 3,3-DBF demonstrated antinociceptive effects in the hot plate test without inducing tolerance. Locomotor activity and motor coordination tests (evaluated through the inverted screen and rotarod tests) revealed no significant differences between the 3,3-DBF-treated and control groups. The gastrointestinal transit assay indicated that 3,3-DBF did not induce constipation, in contrast to morphine. Furthermore, withdrawal signs assessed with the Gellert-Holtzman scale were not comparable to morphine. Additionally, 3,3-DBF exhibited antidepressant-like activity, reducing immobility time in the forced swimming and tail suspension tests, akin to imipramine. In summary, 3,3-DBF demonstrated antinociceptive effects without inducing tolerance or dependence and exhibited antidepressant properties. These findings highlight the potential of 3,3-DBF as a promising therapeutic agent for pain management and its comorbidities, offering advantages over morphine by minimizing side effects.

Asunto(s)

Analgésicos , Antidepresivos , Flavonoides , Morfina , Animales , Morfina/farmacología , Morfina/uso terapéutico , Ratones , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Antidepresivos/química , Masculino , Analgésicos/farmacología , Analgésicos/uso terapéutico , Analgésicos/química , Flavonoides/farmacología , Flavonoides/uso terapéutico , Flavonoides/química , Dolor/tratamiento farmacológico , Manejo del Dolor/métodos , Actividad Motora/efectos de los fármacos

RESUMEN

BACKGROUND: Recently, we demonstrated that nicorandil inhibits mechanical allodynia induced by paclitaxel. In the present study, we evaluated the effect induced by nicorandil in a model of neuropathic pain induced by chronic constriction injury (CCI) in mice. We also investigated putative mechanisms underlying such an effect. METHODS: CCI was induced by three ligatures of the left sciatic nerve. Mechanical allodynia was evaluated by measuring the paw withdrawal threshold with an electronic von Frey apparatus. Concentrations of cytokines and myeloperoxidase activity were determined in the paw tissue, sciatic nerve, and dorsal root ganglia (DRG). RESULTS: Oral administration of two doses of nicorandil (150 mg/kg po), but not equimolar doses of nicotinamide or nicotinic acid, attenuated mechanical allodynia induced by CCI. Nicorandil activity was reduced by previous administration of glibenclamide (40 mg/kg) or naltrexone (5 mg/kg or 10 mg/kg). Two doses of nicorandil (150 mg/kg, po) reduced tumor necrosis factor-α, interleukin-1ß and interleukin-6, but not CXCL-1, concentrations in the paw tissue of CCI mice. Two doses of nicorandil (150 mg/kg, po) reduced concentrations of all these mediators in the sciatic nerve and DRG. Two doses of nicorandil (150 mg/kg, po) also reduced the myeloperoxidase activity in the paw tissue, sciatic nerve, and DRG. CONCLUSIONS: Nicorandil exhibits antiallodynic activity in a model of neuropathic pain induced by CCI. Inhibition of cytokines production and reduction of neutrophils recruitment in paw tissue, sciatic nerve, and DRG as well as activation of ATP-dependent potassium channels and opioidergic pathways, underlie nicorandil antiallodynic activity.

Asunto(s)

Citocinas , Modelos Animales de Enfermedad , Ganglios Espinales , Hiperalgesia , Canales KATP , Neuralgia , Nicorandil , Nervio Ciático , Animales , Nicorandil/farmacología , Neuralgia/tratamiento farmacológico , Neuralgia/metabolismo , Ganglios Espinales/metabolismo , Ganglios Espinales/efectos de los fármacos , Ratones , Nervio Ciático/efectos de los fármacos , Nervio Ciático/metabolismo , Masculino , Citocinas/metabolismo , Canales KATP/metabolismo , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/metabolismo , Gliburida/farmacología , Naltrexona/farmacología , Naltrexona/análogos & derivados , Peroxidasa/metabolismo , Infiltración Neutrófila/efectos de los fármacos , Analgésicos/farmacología

RESUMEN

PURPOSE: Bioactive molecules are relevant to fight cancer and associated conditions. Quinoxaline is a privileged N-heterocycle, notably as anticancer agents. Herein, we report the evaluation of the quinoxaline derivatives DEQX and OAQX as anticancer agents, as well as in function of their anti-inflammatory and analgesic activities. METHODS: Quinoxalines were synthesized and tested as anticancer agents based on cell viability and Annexin V-FITC apoptosis. Anti-inflammatory activity was evaluated from mouse carrageenan peritonitis and levels of interleukin (IL)-1ß and tumor necrosis factor (TNF)-alfa for enzyme-linked immunosorbent assay. Hot-plate and acetic acid-induced writing test were employed to investigate analgesia. RESULTS: Both reduced the Ht-29 cell viability in a dependent-concentration manner (p < 0.001). Total apoptosis was detected for cells treated with 12.5 and 25 µg/mL of both the compounds for 24 and 48 h (all doses, p < 0.0001). DEQX (all doses, p < 0.01) and OAQX (all doses, p < 0.001) acted in leukocyte migration and decreased the IL-1ß and TNF-ß levels (p < 0.05). DEQX (all doses, p < 0.05) and OAQX (5mg/kg, p < 0.001) showed peripheral analgesic effect. CONCLUSIONS: In-vitro and in-vivo results suggest that these quinoxalines are promising for application in pharmacological area due to their anticancer, anti-inflammatory, and peripheric analgesia.

Asunto(s)

Analgésicos , Antiinflamatorios , Antineoplásicos , Apoptosis , Supervivencia Celular , Quinoxalinas , Animales , Quinoxalinas/farmacología , Quinoxalinas/uso terapéutico , Analgésicos/farmacología , Analgésicos/uso terapéutico , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Antineoplásicos/farmacología , Ratones , Apoptosis/efectos de los fármacos , Humanos , Supervivencia Celular/efectos de los fármacos , Interleucina-1beta/metabolismo , Factor de Necrosis Tumoral alfa/análisis , Masculino , Células HT29 , Ensayo de Inmunoadsorción Enzimática , Peritonitis/tratamiento farmacológico

RESUMEN

Eugenia flavescens is a species cultivated in Brazil for food purposes. Given the potential application of essential oils from plants of the genus Eugenia, this study was carried out to investigate the chemical composition, acute toxicity, antioxidant, antinociceptive, gastroprotective activities, and possible mechanisms of action of the essential oil from the leaves of E. flavescens (EOEf). The EOEf was extracted by hydrodistillation, and the chemical composition was obtained using gas chromatography-mass spectrometry. The antioxidant activity was evaluated, as well as the acute toxicity and the antinociceptive and anti-inflammatory effects in mice. In addition, the gastroprotective effect was investigated using an acute gastric lesion model, considering possible mechanisms of action. The major components found in the EOEf were guaiol (19.97%), germacrene B (12.53%), bicyclogermacrene (11.11%), and E-caryophyllene (7.53%). The EOEf did not cause signs of toxicity in the acute oral toxicity test and showed in vitro antioxidant activity with IC50 ranging from 247.29 to 472.39 µg/mL in the tests ABTS and DPPH. In the nociceptive test, EOEf showed a 72.05% reduction in nociception at a dose of 100 mg/kg. In evaluating the anti-inflammatory effect, the essential oil inhibited paw edema by 95.50% and 97.69% at doses of 50 and 100 mg/kg. The results showed that EOEf has a gastroprotective effect, acting through the sulfhydryl compounds (-SH), nitric oxide (NO), and synthesis PGE2 pathways. The results suggested that EOEf is a promising source of constituents with antioxidant, antinociceptive, anti-inflammatory, and gastroprotective properties with application in the food and pharmaceutical industries.

Asunto(s)

Analgésicos , Antiinflamatorios , Antioxidantes , Etanol , Eugenia , Inflamación , Aceites Volátiles , Dolor , Hojas de la Planta , Úlcera Gástrica , Animales , Úlcera Gástrica/tratamiento farmacológico , Úlcera Gástrica/inducido químicamente , Aceites Volátiles/farmacología , Ratones , Hojas de la Planta/química , Analgésicos/farmacología , Analgésicos/aislamiento & purificación , Antioxidantes/farmacología , Masculino , Antiinflamatorios/farmacología , Antiinflamatorios/aislamiento & purificación , Dolor/tratamiento farmacológico , Dolor/inducido químicamente , Eugenia/química , Inflamación/tratamiento farmacológico , Brasil , Antiulcerosos/farmacología , Antiulcerosos/aislamiento & purificación , Femenino

RESUMEN

This is a nonclinical, controlled, and triple-blind study to investigate the effects of codeine-associated geraniol on the modulation of orofacial nociception and its potential central nervous system depressing effect in an animal model. The orofacial antinociceptive activity of geraniol in combination with codeine was assessed through the following tests: (i) formalin-induced pain, (ii) glutamate-induced pain, and (iii) capsaicin-induced pain. Six animals were equally distributed into six groups and received the following treatments, given intraperitoneally (i.p.) 30 minutes before the experiments: a) geraniol/codeine 50/30 mg/kg; b) geraniol/codeine 50/15 mg/kg; c) geraniol/codeine 50/7.5 mg/kg; d) geraniol 50 mg/kg; e) codeine 30 mg/kg (positive control); or f) 0.9% sodium chloride (negative control). We performed pain behavior analysis after the injection of formalin (20 µL, 20%), glutamate (20 µL, 25 µM), and capsaicin (20 µL, 2.5 µg) into the paranasal region. Rubbing time of the paranasal region by the hind or front paw was used as a parameter. In the neurogenic phase of the formalin test, the geraniol/codeine at 50/7.5 mg/kg was able to promote the maximum antinociceptive effect, reducing nociception by 71.9% (p < 0.0001). In the inflammatory phase of the formalin test, geraniol/codeine at 50/30 mg/kg significantly reduced orofacial nociception (p < 0.005). In the glutamate test, geraniol/codeine at 50/30 mg/kg reduced the rubbing time by 54.2% and reduced nociception in the capsaicin test by 66.7% (p < 0.005). Geraniol alone or in combination does not promote nonspecific depressing effects on the central nervous system. Based on our findings, we suggest the possible synergy between geraniol and codeine in the modulation of orofacial pain.

Asunto(s)

Monoterpenos Acíclicos , Analgésicos , Capsaicina , Codeína , Dolor Facial , Dimensión del Dolor , Terpenos , Animales , Codeína/farmacología , Dolor Facial/inducido químicamente , Dolor Facial/tratamiento farmacológico , Monoterpenos Acíclicos/farmacología , Masculino , Dimensión del Dolor/efectos de los fármacos , Capsaicina/farmacología , Terpenos/farmacología , Analgésicos/farmacología , Ratones , Factores de Tiempo , Modelos Animales de Enfermedad , Reproducibilidad de los Resultados , Formaldehído , Ácido Glutámico , Resultado del Tratamiento , Nocicepción/efectos de los fármacos , Análisis de Varianza , Estadísticas no Paramétricas , Conducta Animal/efectos de los fármacos

RESUMEN

Ayapana triplinervis (M.Vahl) R.M.King & H.Rob. (Asteraceae), popularly known as japana, is a tropical, aromatic subshrub widely used as tea to combat some diseases. The essential oil was obtained from the leaves by hydrodistillation (3 h), and the chemical composition was analyzed by gas chromatography coupled to mass spectrometry. For in vivo assays, Mus musculus/Swiss mice were used to evaluate oral acute toxicological (at dose of 2000 mg/kg); peripheral and central analgesic for abdominal contortion (doses of 6.25, 12.5, 25, 50 and 100 mg/kg), hot plate test (12.5, 25, 50, and 100 mg/kg) and formalin (25, 50 and 100 mg/kg); open field test (100 mg/kg); and anti-inflammatory by ear swelling induced by xylene (6.25,12.5, 25, 50, and 100 mg/kg). The yield of A. triplinervis essential oil (AtEO) was 4.6%, and the oxygenated monoterpene 2,5-dimethoxy-p-cymene was the major compound in this study (63.6%). AtEO at a dose of 2,000 mg/kg orally did not change the behavior patterns or mortality of the animals; liver and kidney biochemical levels were similar to the control group, indicating no liver and kidney toxicity. Moreover, AtEO, at doses of 6.25, 12.5, 25, 50, and 100 mg/kg, reduced abdominal contortions by 21%, 54%, 91%, 58%, and 55%, respectively. In the hot plate test, AtEO showed a significant increase in latency time in the 60-min interval at doses of 25 mg/kg (11.3 ± 3.3 s) and 100 mg/kg (11.9 ± 0.9 s). In the first phase of the formalin test, AtEO decreased paw licking time at doses of 25, 50, and 100 mg/kg, with inhibition of 22%, 38%, and 83%; in the second phase, the same doses, decreased licking time with inhibition of 24%, 34%, and 76%. AtEO did not present a significant change in the spontaneous locomotor activity of the animals. Doses of 6.25, 12.5, 25, 50, and 100 mg/kg significantly reduced ear edema induced by topical application of xylene with percentages of 40%, 39%, 54%, 45%, and 45%, respectively. So, AtEO demonstrated low acute oral toxicity and exhibited significant antinociceptive and anti-inflammatory actions, consistent with the use of A. triplinervis in traditional medicine.

Asunto(s)

Analgésicos , Antiinflamatorios , Aceites Volátiles , Animales , Aceites Volátiles/farmacología , Aceites Volátiles/aislamiento & purificación , Ratones , Analgésicos/farmacología , Analgésicos/aislamiento & purificación , Antiinflamatorios/farmacología , Antiinflamatorios/aislamiento & purificación , Brasil , Masculino , Relación Dosis-Respuesta a Droga , Asteraceae/química , Dolor/tratamiento farmacológico , Dolor/inducido químicamente , Edema/tratamiento farmacológico , Edema/inducido químicamente , Hojas de la Planta/química , Benzoquinonas/farmacología , Femenino

RESUMEN

Neuropathic pain is a high-intensity pain that can be caused by compression, transection, injury, nerve infiltration and drug treatment of cancer. Furthermore, drug therapy has low clinical efficacy, many adverse effects and remission of painful symptoms. In this way, natural products derived from plants constitute a promising therapeutic alternative. Therefore, the aim of this study was to evaluate the antihyperalgesic effect of γ-terpinene (γ-TPN) e γ-terpinene in ß-cyclodextrin inclusion complexes (TPN/CD) on neuropathic pain induced by tumor cells. Complexation extended the effect time for another 5 h and daily treatment for six days with γ-TPN (50 mg/kg, p.o.) and γ-TPN/ß-CD (50 mg/kg, p.o.) significantly reduced (p < 0.001) the mechanical hyperalgesia induced by the administration of 2x106 sarcoma cells 180 in the around the sciatic nerve. In addition, the Grip and Rota-rod techniques demonstrated that there was no interference on the muscle strength and motor coordination of the animals, suggesting that the compound under study does not have central nervous system depressant effects at the doses used. Molecular docking studies demonstrate favorable binding energies between γ-TPN and ß-CD, and alpha-2 adrenergic, glutamatergic, opioid and cholinergic receptors. Thus, this study demonstrates the potential of terpinene complexation in controlling neuropathic pain induced by tumor cells.

Asunto(s)

Monoterpenos Ciclohexánicos , Hiperalgesia , Monoterpenos , Neuralgia , beta-Ciclodextrinas , Animales , beta-Ciclodextrinas/química , beta-Ciclodextrinas/administración & dosificación , Neuralgia/tratamiento farmacológico , Hiperalgesia/tratamiento farmacológico , Masculino , Monoterpenos/farmacología , Monoterpenos/química , Monoterpenos/administración & dosificación , Ratones , Analgésicos/farmacología , Analgésicos/química , Analgésicos/administración & dosificación , Modelos Animales de Enfermedad , Nervio Ciático/efectos de los fármacos , Nervio Ciático/lesiones , Línea Celular Tumoral , Simulación del Acoplamiento Molecular , Sarcoma 180/tratamiento farmacológico , Sarcoma 180/patología

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Plant vernacular names can provide clues about the popular use of a species in different regions and are valuable sources of information about the culture or vocabulary of a population. Several medicinal plants in Brazil have received names of medicines and brand-name products. AIM OF THE STUDY: The present work aimed to evaluate the chemical composition and pharmacological activity in the central nervous system of three species known popularly by brand names of analgesic, anti-inflammatory, antispasmodic, and digestive drugs. MATERIALS AND METHODS: Hydroethanolic extracts of Alternanthera dentata (AD), Ocimum carnosum (OC), and Plectranthus barbatus (PB) aerial parts were submitted to phytochemical analysis by HPLC-PAD-ESI-MS/MS and evaluated in animal models at doses of 500 and 1000 mg/kg. Mice were tested on hot plate, acetic acid-induced writing, formalin-induced licking, and intestinal transit tests. Aspirin and morphine were employed as standard drugs. RESULTS: The three extracts did not change the mice's response on the hot plate. Hydroethanolic extracts of AD and PB reduced the number of writhes and licking time, while OC was only effective on the licking test at dose of 1000 mg/kg. In addition, AD and OC reduced intestinal transit, while PB increased gut motility. CONCLUSIONS: Pharmacological tests supported some popular uses, suggesting peripheral antinociceptive and anti-inflammatory effects, while the phytochemical analysis showed the presence of several flavonoids in the three hydroethanolic extracts and steroids in PB, with some barbatusterol derivatives described for the first time in the species.

Asunto(s)

Amaranthaceae , Analgésicos , Antiinflamatorios , Parasimpatolíticos , Fitoquímicos , Componentes Aéreos de las Plantas , Extractos Vegetales , Plectranthus , Animales , Extractos Vegetales/farmacología , Extractos Vegetales/química , Analgésicos/farmacología , Analgésicos/química , Ratones , Parasimpatolíticos/farmacología , Antiinflamatorios/farmacología , Antiinflamatorios/química , Masculino , Amaranthaceae/química , Plectranthus/química , Fitoquímicos/farmacología , Fitoquímicos/análisis , Dolor/tratamiento farmacológico , Ocimum/química , Espectrometría de Masas en Tándem , Brasil , Tránsito Gastrointestinal/efectos de los fármacos

RESUMEN

Noradrenaline (NA) and serotonin (5-HT) induce nociception and antinociception. This antagonistic effect can be explained by the dose and type of activated receptors. We investigated the existence of synergism between the noradrenergic and serotonergic systems during peripheral antinociception. The paw pressure test was performed in mice that had increased sensitivity by intraplantar injection of prostaglandin E2 (PGE2). Noradrenaline (80 ng) administered intraplantarly induced an antinociceptive effect, that was reversed by the administration of selective antagonists of serotoninergic receptors 5-HT1B isamoltan, 5-HT1D BRL15572, 5-HT2A ketanserin, 5-HT3 ondansetron, but not by selective receptor antagonist 5-HT7 SB-269970. The administration of escitalopram, a serotonin reuptake inhibitor, potentiated the antinociceptive effect at a submaximal dose of NA. These results, indicate the existence of synergism between the noradrenergic and serotonergic systems in peripheral antinociception in mice.

Asunto(s)

Norepinefrina , Receptores de Serotonina , Antagonistas de la Serotonina , Serotonina , Animales , Ratones , Norepinefrina/metabolismo , Serotonina/metabolismo , Antagonistas de la Serotonina/farmacología , Masculino , Receptores de Serotonina/metabolismo , Dinoprostona/metabolismo , Citalopram/farmacología , Nocicepción/efectos de los fármacos , Analgésicos/farmacología , Ondansetrón/farmacología , Ketanserina/farmacología , Dolor/tratamiento farmacológico , Dolor/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: In Brazilian popular medicine, Lippia alba leaves are used in teas to treat pain and inflammatory diseases. AIM OF THE STUDY: to evaluate the chemical composition, antinociceptive, and anti-inflammatory activities of Lippia alba essential oil and its major compound geraniol. MATERIAL AND METHODS: Lippia alba leaves were collected in Pará state, Brazil. The leaf essential oil was obtained using a modified Clevenger-type extractor. Then, the oil was analyzed by GC and GC-MS analyses. To evaluate the toxicity of LaEO and geraniol, the doses of 50, 300, and 2000 mg/kg were used in a mouse model. For antinociception tests, abdominal contortion, hot plate, and formalin tests were used; all groups were treated with LaEO and geraniol at doses of 25, 50, and 100 mg/kg; and to evaluate inflammation using the ear edema model. RESULTS: The constituents identified in the highest content were oxygenated monoterpenes: geraniol (37.5%), geranial (6.7%) and neral (3.8%). The animals treated with LaEO and geraniol demonstrated atypical behaviors with aspects of lethargy and drowsiness, characteristics of animals in a state of sedation; the relative weights showed no significant difference compared to the controls. In the abdominal contortion test, LaEO at 25 mg/kg, 50 mg/kg doses, and 100 mg/kg reduced the number of contortions, representing a percentage reduction of 84.64%, 81.23%, and 66.21% respectively. In the hot plate test, LaEO and geraniol increased the latency time at doses of 25, 50, and 100 mg/kg in all test periods; there was no statistical difference between LaEO and geraniol. In the first phase of the formalin test, only doses of 25 mg/kg and 100 mg/kg of LaEO showed significant activity, reducing the latency time by 53.40% and 58.90%. LaEO at doses of 25 mg/kg and 100 mg/kg reduced the size of the edema, demonstrating an anti-inflammatory activity of 59.38% (25 mg/kg) and 50% (100 mg/kg). CONCLUSION: Lippia alba essential oil and geraniol showed central/peripheral analgesic and anti-inflammatory potential and can be used as an alternative or complementary treatment to conventional drugs. More studies are needed to evaluate its action mechanisms and its analgesic effects.

Asunto(s)

Monoterpenos Acíclicos , Analgésicos , Antiinflamatorios , Edema , Lippia , Aceites Volátiles , Hojas de la Planta , Animales , Lippia/química , Aceites Volátiles/farmacología , Aceites Volátiles/química , Brasil , Analgésicos/farmacología , Analgésicos/aislamiento & purificación , Ratones , Antiinflamatorios/farmacología , Antiinflamatorios/aislamiento & purificación , Masculino , Hojas de la Planta/química , Edema/tratamiento farmacológico , Edema/inducido químicamente , Monoterpenos Acíclicos/farmacología , Plantas Medicinales/química , Dolor/tratamiento farmacológico , Conducta Animal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Dimensión del Dolor/efectos de los fármacos

RESUMEN

Burns are a global health problem and can be caused by several factors, including ultraviolet (UV) radiation. Exposure to UVB radiation can cause sunburn and a consequent inflammatory response characterised by pain, oedema, inflammatory cell infiltration, and erythema. Pharmacological treatments available to treat burns and the pain caused by them include nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, antimicrobials and glucocorticoids, which are associated with adverse effects. Therefore, the search for new therapeutic alternatives is needed. Diosmetin, an aglycone of the flavonoid diosmin, has antinociceptive, antioxidant and anti-inflammatory properties. Thus, we evaluated the antinociceptive and anti-inflammatory effects of topical diosmetin (0.01, 0.1 and 1%) in a UVB radiation-induced sunburn model in mice. The right hind paw of the anaesthetised mice was exposed only once to UVB radiation (0.75 J/cm2) and immediately treated with diosmetin once a day for 5 days. The diosmetin antinociceptive effect was evaluated by mechanical allodynia and pain affective-motivational behaviour, while its anti-inflammatory activity was assessed by measuring paw oedema and polymorphonuclear cell infiltration. Mice exposed to UVB radiation presented mechanical allodynia, increased pain affective-motivational behaviour, paw oedema and polymorphonuclear cell infiltration into the paw tissue. Topical Pemulen® TR2 1% diosmetin reduced the mechanical allodynia, the pain affective-motivational behaviour, the paw oedema and the number of polymorphonuclear cells in the mice's paw tissue similar to that presented by Pemulen® TR2 0.1% dexamethasone. These findings indicate that diosmetin has therapeutic potential and may be a promising strategy for treating patients experiencing inflammatory pain, especially those associated with sunburn.

Asunto(s)

Antiinflamatorios , Modelos Animales de Enfermedad , Flavonoides , Inflamación , Nocicepción , Quemadura Solar , Rayos Ultravioleta , Animales , Quemadura Solar/tratamiento farmacológico , Quemadura Solar/patología , Ratones , Rayos Ultravioleta/efectos adversos , Inflamación/tratamiento farmacológico , Masculino , Antiinflamatorios/farmacología , Antiinflamatorios/administración & dosificación , Flavonoides/farmacología , Flavonoides/administración & dosificación , Nocicepción/efectos de los fármacos , Administración Tópica , Analgésicos/farmacología , Analgésicos/administración & dosificación , Edema/tratamiento farmacológico , Hiperalgesia/tratamiento farmacológico

RESUMEN

The present study aimed to evaluate the possible peripheral H2O2-induced antinociception and determine the involvement of opioidergic, cannabinoidergic and nitrergic systems, besides potassium channels in its antinociceptive effect. Prostaglandin E2 was used to induce hyperalgesia in male Swiss mice using the mechanical paw pressure test. H2O2 (0.1, 0.2, 0.3 µg/paw) promoted a dose-dependent antinociceptive effect that was not observed in contralateral paw. Female mice also showed antinociception in the model. The partial H2O2-induced antinociception was potentiated by the inhibitor of catalase enzyme, aminotriazole (40, 60, 80 µg/paw). The antinociception was not reversed by opioid and cannabinoid receptor antagonists naloxone, AM 251 and AM 630. The involvement of nitric oxide (NO) was observed by the reversal of H2O2-induced antinociception using the non-selective inhibitor of nitric oxide synthases L-NOarg and by inhibition of iNOS (L-NIL), eNOS (L-NIO) and nNOS (L-NPA). ODQ, a cGMP-forming enzyme selective inhibitor, also reversed the antinociception. The blockers of potassium channels voltage-gated (TEA), ATP-sensitive (glibenclamide), large (paxillin) and small (dequalinium) conductance calcium-activated were able to revert H2O2 antinociception. Our data suggest that H2O2 induced a peripheral antinociception in mice and the NO pathway and potassium channels (voltage-gated, ATP-sensitive, calcium-activated) are involved in this mechanism. However, the role of the opioid and cannabinoid systems was not evidenced.

Asunto(s)

Analgésicos , Peróxido de Hidrógeno , Animales , Peróxido de Hidrógeno/metabolismo , Masculino , Ratones , Femenino , Analgésicos/farmacología , Óxido Nítrico/metabolismo , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/inducido químicamente , Hiperalgesia/metabolismo , Relación Dosis-Respuesta a Droga , Dinoprostona/metabolismo

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Syagrus coronata, a palm tree found in northeastern Brazil, popularly known as licuri, has socioeconomic importance for the production of vegetable oil rich in fatty acids with nutritional and pharmacological effects. Licuri oil is used in traditional medicine to treat inflammation, wound healing, mycosis, back discomfort, eye irritation, and other conditions. AIM OF THE STUDY: The study aimed to evaluate the antinociceptive, anti-inflammatory, and antipyretic effects of treatment with Syagrus coronata fixed oil (ScFO), as well as to determine the safety of use in mice. MATERIALS AND METHODS: Initially, the chemical characterization was performed by gas chromatography-mass spectrometry. Acute single-dose oral toxicity was evaluated in mice at a dose of 2000 mg/kg. Antinociceptive activity was evaluated through abdominal writhing, formalin, and tail dipping tests, and the anti-inflammatory potential was evaluated through the model of acute inflammation of ear edema, peritonitis, and fever at concentrations of 25, 50, and 100 mg/kg from ScFO. RESULTS: In the chemical analysis of ScFO, lauric (43.64%), caprylic (11.7%), and capric (7.2%) acids were detected as major. No mortality or behavioral abnormalities in the mice were evidenced over the 14 days of observation in the acute toxicity test. ScFO treatment decreased abdominal writhing by 27.07, 28.23, and 51.78% at 25, 50, and 100 mg/kg. ScFO demonstrated central and peripheral action in the formalin test, possibly via opioidergic and muscarinic systems. In the tail dipping test, ScFO showed action from the first hour after treatment at all concentrations. ScFO (100 mg/kg) reduced ear edema by 63.76% and leukocyte and neutrophil migration and IL-1ß and TNF-α production in the peritonitis test. CONCLUSION: Mice treated with ScFO had a reduction in fever after 60 min at all concentrations regardless of dose. Therefore, the fixed oil of S. coronata has the potential for the development of new pharmaceutical formulations for the treatment of pain, inflammation, and fever.

Asunto(s)

Analgésicos , Antiinflamatorios , Edema , Aceites de Plantas , Animales , Analgésicos/farmacología , Analgésicos/aislamiento & purificación , Analgésicos/toxicidad , Ratones , Antiinflamatorios/farmacología , Antiinflamatorios/aislamiento & purificación , Aceites de Plantas/farmacología , Masculino , Edema/tratamiento farmacológico , Edema/inducido químicamente , Dolor/tratamiento farmacológico , Peritonitis/tratamiento farmacológico , Antipiréticos/farmacología , Arecaceae/química , Femenino , Inflamación/tratamiento farmacológico , Inflamación/inducido químicamente , Fiebre/tratamiento farmacológico , Fiebre/inducido químicamente , Administración Oral , Modelos Animales de Enfermedad

RESUMEN

OBJECTIVES: This work investigated the acute antinociceptive effect of a synthetic chalcone, 4-dimethylamino chalcone (DMAC), as well as its effects on vincristine-induced peripheral neuropathy (VIPN) in mice. METHODS: The inhibitory activity of myeloperoxidase was assessed by measuring HOCl formation. Formalin and hot plate tests were used to study the acute antinociceptive effect of DMAC. VIPN was induced through the administration of vincristine sulphate (0.1 mg/kg, i.p., 14 days). Then, DMSO, DMAC (10 or 30 mg/kg; i.p.), or pregabalin (10 mg/kg, i.p.) were administered for 14 consecutive days. Thermal hyperalgesia and mechanical allodynia were evaluated before and after VIPN induction and on days 1, 3, 7, and 14 of treatment. Neurodegeneration and neuroinflammation were assessed through immunohistochemistry for NF200, iNOS, and arginase-1 within the sciatic nerve. KEY FINDINGS: DMAC inhibited myeloperoxidase activity in vitro and presented an acute antinociceptive effect in both formalin and hot plate tests, with the involvement of muscarinic and opioid receptors. Treatment with 30 mg/kg of DMAC significantly attenuated thermal hyperalgesia and mechanical allodynia and prevented macrophage proinflammatory polarisation in VIPN mice. CONCLUSIONS: Our results show that DMAC, acting through different mechanisms, effectively attenuates VIPN.

Asunto(s)

Analgésicos , Chalconas , Hiperalgesia , Neuralgia , Peroxidasa , Animales , Ratones , Masculino , Analgésicos/farmacología , Neuralgia/tratamiento farmacológico , Hiperalgesia/tratamiento farmacológico , Peroxidasa/metabolismo , Chalconas/farmacología , Vincristina/farmacología , Modelos Animales de Enfermedad , Dolor Agudo/tratamiento farmacológico , Nervio Ciático/efectos de los fármacos

RESUMEN

This study carried out to investigate the anti-inflammatory and antinociceptive effect of tropane alkaloid (EB7) isolated from E. bezerrae. It evaluated the toxicity and possible involvement of ion channels in the antinociceptive effect of EB7, as well as its anti-inflammatory effect in adult zebrafish (Zfa). Docking studies with EB7 and COX-1 and 2 were also performed. The tested doses of EB7 (4, 20 and 40 mg/kg) did not show any toxic effect on Zfa during the 96h of analysis (LD50>40 mg/kg). They did not produce any alteration in the locomotor behavior of the animals. Furthermore, EB7 showed promising pharmacological effects as it prevented the nociceptive behavior induced by hypertonic saline, capsaicin, formalin and acid saline. EB7 had its analgesic effect blocked by amiloride involving the neuromodulation of ASICs in Zfa. In evaluating the anti-inflammatory activity, the edema induced by κ-carrageenan 3.5 % was reduced by the dose of 40 mg/kg of EB7 observed after the fourth hour of analysis, indicating an effect similar to that of ibuprofen. Molecular docking results indicated that EB7 exhibited better affinity energy when compared to ibuprofen control against the two evaluated targets binding at different sites in the cocrystallized COX-1 and 2 inhibitors.

Asunto(s)

Analgésicos , Simulación del Acoplamiento Molecular , Pez Cebra , Animales , Analgésicos/farmacología , Analgésicos/química , Analgésicos/aislamiento & purificación , Tropanos/farmacología , Tropanos/aislamiento & purificación , Tropanos/química , Edema/tratamiento farmacológico , Edema/inducido químicamente , Carragenina/farmacología , Ciclooxigenasa 2/metabolismo , Ciclooxigenasa 1/metabolismo , Bignoniaceae/química , Relación Dosis-Respuesta a Droga , Relación Estructura-Actividad , Alcaloides/farmacología , Alcaloides/aislamiento & purificación , Alcaloides/química , Canales Iónicos Sensibles al Ácido/metabolismo , Canales Iónicos Sensibles al Ácido/química , Antiinflamatorios no Esteroideos/farmacología , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/aislamiento & purificación , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antiinflamatorios/aislamiento & purificación , Estructura Molecular

RESUMEN

Fibromyalgia (FM) is a painful chronic condition that significantly impacts the quality of life, posing challenges for clinical management. Given the difficulty of understanding the pathophysiology and finding new therapeutics, this study explored the effects of a medicinal plant, E. brasiliensis, in an FM model induced by reserpine in Swiss mice. Animals were treated with saline 0.9% (vehicle), duloxetine 10 mg/kg (positive control), or hydroalcoholic extract of E. brasiliensis leaves 300 mg/kg (HEEb). Nociceptive parameters, as well as locomotion, motor coordination, strength, anxiety, and depressive-like behaviors, were evaluated for 10 days. After that, the brain and blood were collected for further analysis of cytokines (interleukin 1? and interleukin 6), brain-derived neurotrophic factor (BDNF), and the immunocontents of total and phosphorylated Tropomyosin receptor kinase B (TrkB). The results demonstrated that the acute and prolonged treatment with HEEb was able to reduce both mechanical and thermal nociception. It was also possible to observe an increase in the strength, without changing locomotion and motor coordination parameters. Interestingly, treatment with HEEb reduces anxious and depressive-like behaviors. Finally, we observed a reduction in inflammatory cytokines in the hippocampus of animals treated with HEEb, while an increase in BDNF was observed in the prefrontal cortex (PFC). However, no alterations related to total and phosphorylated TrkB receptor expression were found. Our study demonstrated the antinociceptive and emotional effects of HEEb in mice, possibly acting on neuroinflammatory and neurotrophic mechanisms. These data provide initial evidence about the E. brasiliensis potential for treating chronic pain.

Asunto(s)

Analgésicos , Antiinflamatorios , Factor Neurotrófico Derivado del Encéfalo , Modelos Animales de Enfermedad , Fibromialgia , Extractos Vegetales , Hojas de la Planta , Reserpina , Animales , Analgésicos/farmacología , Analgésicos/uso terapéutico , Ratones , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Hojas de la Planta/química , Fibromialgia/tratamiento farmacológico , Fibromialgia/inducido químicamente , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Masculino , Receptor trkB/metabolismo , Emociones/efectos de los fármacos , Citocinas/metabolismo , Depresión/tratamiento farmacológico , Depresión/inducido químicamente , Ansiedad/tratamiento farmacológico , Ansiedad/inducido químicamente , Conducta Animal/efectos de los fármacos

RESUMEN

Baccharin is one of the major compounds found in Brazilian green propolis and its botanical source, Baccharis dracunculifolia. Considering the biological effects of propolis and B. dracunculifolia, this study aims to evaluate the analgesic and anti-inflammatory potential of baccharin. The neurodepressor potential was performed by the open field test, analgesia by mechanical stimulation with Dynamic Plantar Aesthesiometer, and by thermal stimulation with Hargreaves apparatus. In addition, the anti-inflammatory potential was achieved by the paw edema assay, histopathological evaluation, and NF-kB expression. Doses of 2.5, 5, and 10 mg/kg of baccharin were evaluated. After euthanasia, plantar tissue was collected and prepared for histology. As a result, analgesic activity was observed at a dose of 10 mg/kg of baccharin in thermal stimulation under an inflammatory process and anti-inflammatory potential at a dose of 5 mg/kg of baccharin from the second hour in the paw edema test. A decrease in cellular infiltrate and down-modulation of NF-kB, besides the reduction of edema in the histopathology was observed. There was no evidence of kidney and liver toxicity and neurodepressive potential at the doses tested. Thus, baccharin has a promising anti-inflammatory effect possibly associated with antiedematogenic activity by inhibiting mediators such as prostaglandins, inhibiting the migration of polymorphonuclear cells, and modulating NF-kB expression.

Asunto(s)

Analgésicos , Antiinflamatorios , Baccharis , Edema , FN-kappa B , Própolis , Animales , Masculino , Ratas , Analgésicos/farmacología , Antiinflamatorios/farmacología , Antiinflamatorios/aislamiento & purificación , Baccharis/química , Brasil , Edema/tratamiento farmacológico , Edema/inducido químicamente , FN-kappa B/metabolismo , Própolis/farmacología , Ratas Wistar , Tricotecenos

RESUMEN

This is the first study to analyze the anti-inflammatory and antinociceptive effect of withanicandrin, isolated from Datura Ferox leaves, and the possible mechanism of action involved in adult zebrafish (ZFa). To this end, the animals were treated intraperitoneally (i. p.) with withanicandrin (4; 20 and 40 mg/kg; 20 µL) and subjected to locomotor activity and acute toxicity. Nociception tests were also carried out with chemical agents, in addition to tests to evaluate inflammatory processes induced by κ-Carrageenan 1.5 % and a Molecular Docking study. As a result, withanicandrin reduced nociceptive behavior by capsaicin at a dose of 40 mg/kg and by acid saline at doses of 4 and 40 mg/kg, through neuromodulation of TRPV1 channels and ASICs, identified through blocking the antinociceptive effect of withanicandrin by the antagonists capsazepine and naloxone. Furthermore, withanicandrin caused an anti-inflammatory effect through the reduction of abdominal edema, absence of leukocyte infiltrate in the liver tissue and reduction of ROS in thel liver tissue and presented better affinity energy compared to control morphine (TRPV1) and ibuprofen (COX-1 and COX-2).

Asunto(s)

Analgésicos , Pez Cebra , Animales , Analgésicos/farmacología , Analgésicos/química , Analgésicos/aislamiento & purificación , Canales Iónicos Sensibles al Ácido/metabolismo , Simulación del Acoplamiento Molecular , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antiinflamatorios/aislamiento & purificación , Carragenina , Relación Estructura-Actividad , Relación Dosis-Respuesta a Droga , Canales Catiónicos TRPV/antagonistas & inhibidores , Canales Catiónicos TRPV/metabolismo , Edema/tratamiento farmacológico , Edema/inducido químicamente , Hojas de la Planta/química , Estructura Molecular